VASCULAR AND MONOCYTE DYSFUNCTION AND LOCAL INFECTION

晚期糖基化终产物(AGEs)的组织和血管沉积 蛋白质和脂类发生不可逆的糖氧化产物 在正常衰老过程中，由于葡萄糖耐量不足而加速， 动脉粥样硬化和肾功能不全。因此，宿主响应机制 由局部炎症和/或感染引发的工作在年龄较大的 这些设置中的环境。对解决此类问题至关重要的细胞 炎症灶，特别是内皮细胞和单核细胞 吞噬细胞(MPS)，AGEs表达受体(RAGE)，一个主要细胞 AGEs的表面结合部位。随着年龄的增长而订婚，愤怒 带来局部炎症由以下因素引发的变化 糖耐量试验检测富含AGE组织中的牙龈卟啉单胞菌 动物也同样受到PG的挑战。葡萄糖不耐受小鼠的牙周组织 AGEs广泛沉积，RAGE表达增加 国会议员和欧洲议会议员。中断AGE与细胞RAGE的相互作用，通过 管理，通过管理一种截断形式的愤怒(愤怒) 跨越细胞外域，抑制牙周炎和 牙槽骨丢失。我们假设年龄，通过他们与 内皮细胞和单核细胞的愤怒，为一种夸张的牙龈组织 炎症反应最终导致牙槽骨丢失增加。因此， 葡萄糖耐受小鼠的牙周炎提供了一个扩展的机会 我们的概念是年龄-RAGE介导的细胞激活作为非 消解和破坏性炎症。我们的目标是：(1)比较 炎症细胞因子的产生，胶原的合成和降解， 炎症细胞进入受影响的牙龈组织和程度 糖耐量低减和正常小鼠有无牙槽骨丢失 感染Pg；(2)确定阻断年龄-愤怒的相互作用 减轻牙周炎和骨质流失；以及，(3)使用小鼠 转基因(TG)模型，其中野生型或显性负性愤怒 在ECs或MPS中选择性过度表达，以测试愤怒的概念 在年龄丰富的牙龈中导致帕金森病。项目将与以下机构密切合作 项目1和2，并将从核心获得技术援助。 协作交互包括：TG的开发和表征 RAGE小鼠(项目1-2和核心C)，RAGE转录分析 RAGE配体结合域的表达和解析(项目1-2)， 细胞因子分析(项目2)和组织病理学研究(核心B)。

Tissue and vascular deposition of Advanced Glycation Endproducts (AGEs), irreversible products of glycoxidation of proteins and lipids, occur during normal aging and are accelerated by glucose intolerance, atherosclerosis and renal dysfunction. Thus, host response mechanisms triggered by local inflammation and/or infection operate in an AGE-rich environment in these settings. Cells critical to resolution of such inflamed foci, especially endothelial cells (ECs) and mononuclear phagocytes (MPs), express Receptor for AGEs (RAGE), a principal cell surface binding site for AGEs. Consequent to engagement by AGEs, RAGE brings about changes in which local inflammation is initiated by porphyromonas gingivalis (Pg) in AGE-rich tissues using glucose intolerant animals similarly challenged with Pg. Gingiva from glucose-intolerant mice showed extensive deposition of AGEs and increased expression of RAGE in MPs and ECs. Interruption of AGE interaction with cellular RAGE, by administration, by administration of a truncated form of RAGE (sRAGE) spanning the extracellular domain, suppressed gingival inflammation and alveolar bone loss. We hypothesize that AGEs, via their interaction with endothelial and monocyte RAGE, prime gingival tissue for an exaggerated inflammatory response eventuating in enhanced alveolar bone loss. Thus, gingivitis in glucose-intolerant mice provides an opportunity to extend our concept of AGE-RAGE-mediated cellular activation as a basis for non- resolving and destructive inflammation. Our aims are: (1) to compare production of inflammatory cytokines, collagen synthesis and degradation, influx of inflammatory cells into affected gingival tissue and extent of alveolar bone loss in glucose-intolerant and normal mice with/without infection with Pg; (2) to determine how blockade of AGE-RAGE interaction attenuates periodontal inflammation and bone loss; and, (3) to use murine transgenic (Tg) models in which wild-type or dominant negative RAGE is selective over-expressed in ECs or MPs to test the concept that RAGE contributes to PD in AGE-rich gingiva. Project will work closely with Projects 1&2 and will obtain technical assistance from the Cores. Collaborative interactions include: development and characterization of Tg RAGE mice (Projects 1-2 and Core C), transcriptional analysis of RAGE expression and dissection of the RAGE ligand binding domain (Project 1-2), cytokine analysis (Project 2), and a pathologic study of tissues (Core B).